Pain is a critical problem in health care: it affects millions of individuals, costs billions of dollars, and is a major cause of morbidity, suffering, and suicide. Although recent research has shown that there may be significant gender differences in responses to acute and chronic pain, no objective test for pain currently exists. Chronic neuropathic pain in particular is difficult to treat because we have little understanding of the altered plasticity in neural circuitry that precedes this condition. To define objective criteria for patients suffering from neuropathic pain, the structural and functional neuronal circuitry of normal male and female subjects during the processing of acute pain must first be understood, and this circuitry compared with that seen in chronic pain states. Our goals are to use functional magnetic resonance imaging (fMRI) to define gender differences in (1) functional activation in the thalamus, anterior cingulate cortex and periaqueductal gray following noxious thermal stimuli; (2) patterns of CNS activation in the thalamus, anterior cingulate cortex and periaqueductal gray following experimental hyperalgesia; and (3) CNS activation in these same regions after morphine, including the effects of morphine on noxious and non-noxious stimuli, and the effects of naloxone precipitated morphine withdrawal on CNS activation. Specifically, we will test the following hypotheses: (1) there will be differences in activation in these regions in male and female subjects; (2) painful stimuli, compared with non-painful stimuli, will specifically and differentially activate somatotopic and limbic regions; (3) following experimental hyperalgesia, normally non-painful stimuli (e.g. brush) will produce activation in the same regions as painful stimuli; (4) opioids will activate regions in the CNS that are involved in descending analgesia, (5) opioids will inhibit CNS activation following noxious heat or hyperalgesia; and (6) naloxone reversal of acute morphine will produce changes in CNS activation similar to those seen in hyperalgesia. These studies are feasible because we have the necessary fMRI facilities and personnel to conduct them, and we have demonstrated our ability to perform the required experiments. With fMRI, repeated studies can be obtained without any exposure to radiation or contrast. Regions of interest to be quantitated for functional activity will include ascending pain pathways associated with somatotopic processing of pain (thalamus), behavioral responses to pain (anterior cingulate cortex), and structures involved in endogenous/descending analgesia (periaqueductal gray). Other regions will be assessed for activation on a post hoc basis. The proposed studies will form the basis of investigations of pain pathways in pre- and post menstrual women, gender differences in neuropathic pain, and gender differences of drug effects on CNS activation.